The invention relates to treatment of cardiovascular diseases. More particularly, the invention involves use of osteoprotegerin (OPG) to treat and prevent cardiovascular diseases associated with occlusion and calcification of blood vessels, such as atherosclerosis.
Development and maintenance of the mammalian skeleton involves the regulation and interaction of its component cell types (Erlebacher et al. Cell 80, 371-380 (1995); Marks, Acta Med Dent Helv 2, 141-157 (1997)). Major contributors to skeletal architecture include chondrocytes which form, cartilage, osteoblasts which synthesize and deposit bone matrix, and osteoclasts which resorb bone. Chondrocytes are derived from mesenchymal cells and function to generate an initial cartilage template required for endochondral bone formation. Osteoblasts, derived from mesenchymal osteoprogenitor cells, are located on the surface of bone where they synthesize, transport and arrange the matrix proteins. Osteoclasts are derived from granulocyte-monocyte precursors present in the hematopoietic marrow (Roodman, Endocrine Rev. 17, 308-332 (1996); Mundy, J. Bone Min. Res. 8, S505-S510 (1993); Manologas and Jilka New Eng. J. Med. 332, 305-311 (1995)). After establishing a tight adherence to the bone surface, osteoclasts form resorption zones that are acidified by a specialized structure known as the ruffled border. The ruffled border functions as a secretory conduit where protons and acid proteases are secreted which decalcify and then digest bone matrix. During the process of osteoclast mediated resorption, it is thought that protein factors are elaborated that act as signaling molecules to initiate bone renewal by osteoblasts. Osteoblasts, in turn, can influence osteoclast function through the expression of soluble or membrane bound regulators (Takahashi et al. Endocrinology 123, 2600-2602 (1988)). The coupling between osteoblast and osteoclast functions is critical for skeletal modeling, remodeling, and repair (Mundy, J. Cell Biochem. 53, 296-300 (1993); Mundy et al. Bone 17, 71S-75S F(1995)).
Postmenopausal osteoporosis, the most common bone disease in the developed world, has been causally linked to estrogen loss (for review, see Pacifici, J. Bone Min. Res. 11, 1043-1051 (1996)). Postmenopausal bone loss can be attributed to loss of regulatory control exerted by estrogen on the production of cytokines and other factors that regulate osteoclast development. The resultant shift in the balance of osteoclast and osteoblast activity favors a net loss of bone mass ultimately leading to osteoporosis.
Osteoporosis in human populations has been associated with a higher incidence of arterial calcification, a component of many atherosclerotic lesions (Parhami and Demer, Curr. Opin. Lipidology 8, 312-314 (1997); Banks et al. Eur. J. Clin. Invest. 24, 813-817 (1994); Parhami et al. Arterioscler. Thromb. Vasc. Biol. 17, 680-687 (1997)). Common factors may underlay the pathogenesis of these two diseases. Indeed some arterial calcium mineral deposits appear identical to fully formed lamellar bone, including trabeculae, lacunae, and islands of marrow (Haust and Geer, Am. J. Pathol. 60, 329-346 (1970); Bunting, J. Exp. Med. 8, 365-376 (1906)). Furthermore, calcified arteries have been shown to express several bone matrix proteins, including collagen Type I, matrix GLA protein, osteocalcin, osteonectin and bone morphogenetic protein type 2 (Bostrom et al. J. Clin. Invest. 91, 1800-1809 (1993); O""Brien et al. Circulation 92, 2163-2168 (1995); Giachelli et al. J. Clin. Invest. 92, 1686-1696 1993); Bostrom et al. Am. J. Cardiol. 75, 88B-91B (1995)). These findings have lead to speculation that arterial calcification is an organized, regulated process with cellular and molecular mechanisms similar to organized bone formation (Demer, Circulation 92, 2029-2032 (1995); Parhami et al. J. Atheroscler. Thromb. 3, 90-94 (1996)).
Osteoprotegerin (OPG), a recently identified member of the tumor necrosis factor receptor gene superfamily, is a secreted factor that inhibits osteoclast development both in vitro and in vivo (Simonet et al. Cell 89, 309-319 (1997); PCT Application No. U.S. Ser. No. 96/20621 (WO97/23614) which is hereby incorporated by reference). Transgenic mice overexpressing OPG in the liver, have high levels of OPG protein in their systemic circulation and exhibit a marked increase in bone density (osteopetrosis). In normal mouse embryos, OPG has been localized within cartilage rudiments of developing bones, as well as in the small intestine and the muscular wall of the aorta and several major arteries.
Given the strong correlation between the occurrence of osteoporosis and the onset of conditions which could lead to cardiovascular disease, particularly disease characterized by arterial calcification, and the similarities in the processes for depositing calcium in bone and along the interior of arterial walls, it is an object of the invention to develop pharmaceutical compositions and methods for the concurrent prevention and treatment of osteoporosis and cardiovascular disease. Development of a single therapeutic for the prevention and treatment of both conditions would greatly enhance the longevity and quality of life of affected patients, by reducing the risk of crippling and possibly fatal bone fractures and, at the same time, preventing or retarding conditions which could lead to hypertension, ischemia, heart attacks, and stroke.
Surprisingly, it has been found that loss of OPG in an OPG knockout animal results in calcification of the aorta and renal arteries, which are sites of endogenous OPG expression in normal animals. These findings implicate OPG in the regulation of pathological calcification of arteries such that, when circulating OPG is absent or present at low levels, accumulation of calcium deposits on arterial walls is greatly accelerated. The presence of normal or above normal levels of OPG (such as in transgenic mice expressing OPG) are not associated with vascular calcification.
The present invention relates to methods and compositions for treating or preventing cardiovascular diseases. The methods comprise administration of a therapeutically effective amount of OPG wherein said amount is sufficient to treat or prevent a cardiovascular disease.
The present invention also relates to OPG compositions useful for treating or preventing cardiovascular disease. OPG compositions are typically pharmaceutically acceptable mixtures suitable for a variety of routes of administration.